The WT1 protein is a sequence-specific DNA-binding transcription factor with an critical role in normal kidney development and the pathogenesis of Wilms' tumor. During the initial funding period the investigators established that WT1 may act as an activator of transcription and that dominant negative forms of WT1 can block activation. The investigators further demonstrated that WT1 can self associate and proposed that non-DNA binding, dominant-negative forms of the WT1 protein shield or sequester wild-type WT1. However, the role of WTl multimerization in its normal function to activate or repress transcription is not clear. The ability of WT1 to activate or repress transcription depends on the nature of the expression vector used in co-transfection experiments. The investigators believe that WT1 is a default activator of transcription and under experimental conditions that deplete WT1 of essential co-factors for activation, WT1 will repress a target gene. Despite much study, the mechanism by which gene regulation is modulated by WT1 remains obscure and the nature of the transcriptional co-factors required for WT1 function is not yet known. In addition it is not known which transcriptional function of WT 1 is critical for its role in controlling differentiation and cellular growth. Tumor associated mutations in WT1 have been isolated in both its minimal activation domain and repression domain. They believe that these mutations interfere with critical protein-protein interactions of WT1 and may serve to genetically identify critical co-factors required for the action of the WT1 protein. During the initial term of this grant they found that WT1 can repress growth and induce epithelial-like differentiation of fibroblasts. This offers us a system in which to study the biological effects of tumor-associated and artificial mutations of WT 1. Such a system may also allow us to determine the biological importance of proteins that closely associate with WT1. Through these aims, by the end of the next period of funding, they will have a much more detailed understanding of the mechanism of action of WT1 in gene regulation, growth suppression and induction of differentiation. They hope to characterize the mechanism(s) by which WT1 represses target genes and identify proteins that interact with WT1 to modulate both its transcriptional and biological effects.
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